Hydroxamic acid derivatives of 1-amino-cyclohexanecarboxylic acid

ABSTRACT

1. A COMPOUND OF THE FOLLOWING FORMULA:   1-R1,2-R2,3-R3,4-R4,5-(H2N-),5-(HO-N(-R5)-CO-),6-R-   CYCLOHEXANE   WHEREIN: R AND R4 ARE SELECTED FROM THE CLASS CONSISTING OF HYDROGEN AND LOWER ALKYL; R1, AND R2 AND R3 ARE SELECTED FROM THE CLASS CONSISTING OF HYDROGEN, AND LOWER ALKYL, WITH THE PROVISO THAT AT LEAST TWO OF R,R1,R2 R3 AND R4 ARE ALWAYS HYDROGEN; R5 IS SELECTED FROM THE CLASS CONSISTING OF HYDROGEN AND LOWER ALKYL; AND THE SALTS THEREOF WITH PHARMACEUTICALLY ACCEPTABLE ACIDS.

United States Patent U.S. Cl. 260-500.5 H 2 Claims ABSTRACT OF THE DISCLOSURE The compounds are hydroxamic acids of alicyclic amino acids and esters of said compounds, all of which have valuable pharmacodynamic properties in that they relieve hyperglycemia in warm-blooded animals.

This application is a continuation-in-part of application Ser. No. 874,382, filed Nov. 5, 1969, now U.S. Pat. 3,703,542.

DESCRIPTION OF THE INVENTION wherein:

each of R, R R, R and R is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen, nitro and amino, with the proviso that at least 2 of R, R R R and R are always hydrogen; and each of R and R is selected from the group consisting of hydrogen, lower alkyl, phenyl and phenyl (lower) alkyl; and the pharmaceutically-accepted acidaddition salts thereof. The phenyl and phenyl(lower) alkyl groups may also be substituted in any one or two positions on the benzene ring by a substituent selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halogen, nitro and amino. Preferred compounds are of the following formula:

wherein R and R are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen, nitro and amino; R R and R are selected from the class consisting of hydrogen and lower alkyl, with the proviso that at least two of R, R R R and R are always hydrogen; R is selected from the class consisting of hydrogen and lower alkyl; and the pharmaceutically-accepted acid-addition salts thereof.

3,845,109 Patented Oct. 29, 1974 Especially preferred compounds are of the following formula:

wherein:

R and R are selected from the class consisting of hydrogen, lower alkyl and lower alkoxy; R R and R are selected from the class consisting of hydrogen and lower alkyl, with the proviso that at least two of R, R R R and R are always hydrogen; and the pharmaceuticallyaccepted acid-addition salts thereof.

The novel compounds of formula (I) above may conveniently be prepared by heat-reacting a selected hydroxylamine derivative with a selected l-aminocyclohexanecarboxylic acid N-carboxyanhydride (NCA) in accordance with the following scheme:

(A) i /CHCH\ o ra -cs 0-0:

011-04 /O+NHRIOR in in HN-o R1 1 2 /CHCH c lv-on o-c-Nmom CH-G wherein R, R R R R, R and R have the same meanings described hereinbefore.

The reactants (III), i.e., the hydroxamic acid derivatives, employed in the preparative process illustrated by the above reaction scheme are known compounds which are readily available from commercial sources. The reactants (II), i.e., the NCAs of the l-aminocycloalkylcarboxylic acids, which are not commercially available, can easily be prepared in accordance with standard organic procedures well known to those skilled in the art. For example, a procedure which has been employed to synthesize the anhydrides of formula II) above is described in U.S. Pat. 3,206,455 Process for Producing 6-(a-aminoacylamino) Penicillanic Acids, H. E. Album and N. H. Grant.

It has been discovered that compounds of formula (I) meeting the described qualifications have valuable pharmacological properties. More specifically, said compounds have been found to have unexpected activity in relieving hyperglycemia in warm-blooded animals as referred to in greater detail hereinafter.

In vivo testing of the new compounds for their hyperglycemic activity is carried out as described in the literature [cf. the article of H. Album and R. L. Fenichel, Nature 213, 515 (1967)] as follows:

After one week on a high-fat, high-protein diet, six male Sprague Dawley rats are fasted for 18 hours. An initial blood sample is taken by cardiac puncture, then 30 mg./kg. of the text compound is given by gavage. Thirty minutes later, the animals are injected intraperitoneally with 1 ml. of buffered cysteine solution containing 5 mg. of reduced insulin B-chain and 5 mg. of albumin. A second identical injection is given at 60 minutes and blood samples are taken at 60, 90, and 140 minutes after the first one. Control groups of six rats are run with B-chainalbumin alone and with compound alone. Compounds showing activity in blocking the B-chain induced hyperglycemia are tested at lower concentrations and the results are expressed as the lowest concentration showing a significant elfect. The compounds of the invention show such effect when administered at 30 mg./kg.

The surprising eflicacy of the compounds of formula (I) above in the test described hereinbefore has clearly indicated that they are active anti-hyperglycemic agents.

In the exercising of the method of the invention, the compouds of formula (I) used therein may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound selected, the chosen route of administration, and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules, which may contain conventional excipients, or in the form of solutions; or they may be injected parenterally, that is intramuscularly, intravenously or subcutaneously. For parenteral administration, they may be used in the form of sterile solutions containing other solutes, for example, enough saline or glucose to make the solutions isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. It will generally be found that when the composition is administered to produce the same effect as a smaller quantity given parenterally. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects.

The compounds (1) of the present invention, when tested in accordance with the test procedure given in detail hereinbefore, are effective to relieve hyperglycemia at dosages in the range of about to about 80 mg./ kg. of body weight of the animals tested.

The following examples are illustrative of the preparation of the novel compounds of the invention which are useful in relieving hyperglycemia in warm-blooded animals:

EXAMPLE I l-Aminocyclohexanecarbohydroxamic Acid Ten grams of hydroxylamine hydrochloride were treated 4 acid reversed the blockage, thereby showing an insulinpreserving hyperglycemic effect.

' EXAMPLE 1r 1-Amino-N-benzyloxycyclohexanecarboxamide Eight grams of O-benzylhydroxylamine hydrochloride were treated with an equivalent amount of sodium methoxide in 100 ml. of methanol, and the sodium chloride was removed. After removal of the methanol, the O- benzylhydroxylamine was dissolved in 200 ml. of tetrahydrofuran, and to it is added a solution of 7.75 g. of N-carboxy-l-aminocyclohexane carboxylic acid anhydride in 100 ml. of tetrahydrofuran. The mixture is allowed to stand at 4 for 4 days and is then filtered. The filtrate is evaporated to dryness and the residue is dissolved in 150 mlof .hQt ethanol. A crystalline product forms on cooling,

The product, which is the titled compound, is an orally effective anti-hyperglycemic agent when tested in accordance with the test procedure described hereinbefore.

EXAMPLE III Following the procedure of Example I, a series of hydroxylamine derivatives are separately reacted with the NCA of 1-aminocyclohexanecarboxylic acid (ACHCA) to obtain the hydroxamic acid derivatives of the latter in the form of their HCl acid-addition salts having anti hyperglycemic activity, as set forth in Table A below:

TABLE A Hydroxylamine Substituted N CA Hydroxamic acid derivadcrivative of 1-ACHCA tive of the amino acid Hydroxylamine. 2-ethyl-1-aminocyelohegaane carboxylic aci 2-ethyl-l-aminocyclohexanecarbohydroxanlic acid.

D0 3-methoxy-l-amino- B-methoxy-l-aminocyclocyclohexane earhexanecarbohydroxamic boxylic acid. acid.

O-ethylhydroxyl- 3-hydroxy-1-amin0- 3-hydroxy-1-amino-N- amine. eyclohexane carethoxycyelohexane boxylie acid. carboxamide.

2-chloro-1-amino-N-propoxycyclohexane carboxamide.

O-propylhydroxyl- 2-chloro-1-aminocycloamine. hexane carboxylic amine. hexane carboxylic oxycyclohexane carboxaci amide. Hydroxylamine 2-propyl-3-ethoxy-1- 2-propyl-3-ethoxy-1-arnin0- aminocyclohexane cyclohexaneearbohycarboxylic acid. droxamic acid.

EXAMPLE IV Following, in this instance, the procedure of Example II, another series of hydroxylamine derivatives are separately reacted with the selected NCAs of l-aminocyclohexane carboxylic acid to obtain the hydroxamic acid derivatives of the latter in the form of their bases which have antihyperglycemic activity, as set forth in Table B below:

TABLE B Substituted NCA of 1-ACH CA Hydroxamic acid deriva- Hydroxylamine tive of the amino acid derivative Z-nitro-l-amino-N-phenoxycyclohexane carboxamide.

3-ethyl-1-amino-N-phenoxycyclohexane carbox- 2-nitro-l-aminocyc1ohexane carboxylic acid.

Do 3-ethyl-1-aminocyclohexane carboxylic O-phenylhydroxylamine.

aci amide. O-benzylhydroxyl- 2,3-dichloro-1-amino- 2,3-dieh1oro-1-amino-N- amine. eyclohexane carbenzyloxycyclohexane boxylie acid. carboxarnide.

EXAMPLE V EXAMPLE VI Following the procedure of Example V, a series of hydroxamic acid derivatives are separately reacted with a selected substituted NCA of l-aminocyclohex ane car boxylic acid to obtain the hydroxamic acid derivatives of the latter in the form of their bases which have said stated activity, as set forth in Table C below:

N-phenoxyhyboxylic acid. carbohydroxamic acid. Z-chloro-baminocyelo- 2-chloro-1-amino-N- droxylamine. hexane carboxylio phenoxy-eyelohexane ac carbohydroxamic acid. N-methyl-O-prol-aminoeyclohexane 1-amino-N-methyl-N- pylhydroxylcarboxylic acid. propoxy-cyclohexane amine. carboxamide.

We c1-a1m:

1. A compound of the following formula:

wherein:

R and R are selected from the class consisting of hydrogen and lower alkyl; R R and R are selected from the class consisting of hydrogen, and lower alkyl, with the proviso that at least two of R, R R R and R are always hydrogen; R is selected from 6 the class consisting of hydrogen and lower alkyl; and the salts thereof with pharmaceutically acceptable acid-s. 2. A compound of the following formula:

R and R are selected from the class consisting of hydrogen and lower alkyl; R R and R are selected from the class consisting of hydrogen and lower alkyl; with the proviso that 'at least two of R, R R R and R are always hydrogen; and the salts thereof with pharmaceutically acceptable acids.

References Cited UNITED STATES PATENTS 3,703,542 11/1972 Alburn et a1. 260500.5 H 3,206,455 9/1965 Alburn et 'al. 260239.1 3,551,574 12/1970 Franberger et a1. 260500.5 H 2,943,092 6/1960 Smit et al. 260500.5 H

JOSEPH E. EVANS, Primary Examiner US. Cl. X.R. 424-315 

1. A COMPOUND OF THE FOLLOWING FORMULA: 